High blood pressure (hypertension) continues to have a major impact on mortality and morbidity in most human populations. This is particularly the case where dietary sodium chloride (salt) intake is high. Thus, the long-term goal of this project is to provide an understanding of the mechanisms by which abnormal regulation of body sodium and water balance promote hypertension development. It is very likely that intrinsic kidney dysfunction plays a key role in this process. The central hypothesis motivating this work, however, is that humoral factors also involved in regulating body fluid volume and electrolyte concentration cause an increase in blood pressure by affecting neural cardiovascular control mechanisms (i.e. brain and autonomic nervous system). The proposed studies will focus on two such factors--angiotensin II and endothelin. Experiments utilizing chronic infusion of these peptides indicate that they influence blood pressure by at least two mechanisms: 1) "fast" pressor effects, primarily due to direct vasoconstriction; and 2) "slow" pressor effects, probably mediated via multiple indirect actions, including activation of neurogenic (sympathetic) pressor responses. High salt intake alone strongly enhances the slow pressor effects of angiotensin II and endothelin. Recent work, moreover, showed that both stenosis of a renal artery and experimental chronic renal failure (reduction in renal mass) also produced such enhancement (to the slow pressor effect of angiotensin II). The experiments proposed in this application will examine the mechanism and implications of these recent findings. All studies will be conducted in conscious Sprague-Dawley rats instrumented for direct, daily measurements of blood pressure and sodium/water balance; and for chronic administration of peptides. Several protocols will seek to establish if renal artery stenosis or reduced renal mass augment slow pressor mechanisms by: 1) affecting plasma peptide concentrations, 2) altering body fluid volume/electrolyte status, or 3) affecting neural input via renal sensory afferents. Others will address the question of how high salt intake is "sensed" by neurogenic pressor mechanisms responsive to angiotensin II and endothelin. The overall role of endothelin in the chronic maintenance of hypertension in rats with reduced renal mass will be assessed using newly developed pharmacological antagonists of endothelin receptors. Finally, a possible contribution of endothelin to angiotensin II induced hypertension will be explored. These investigations should provide new insights into the link between abnormalities in renal function and/or body fluid regulation and the pathogenesis of hypertension.